JP6824432B2 - A pharmaceutical composition for preventing or treating breast cancer containing a polymorph of tetraarsenic hexaoxide and a method for producing the same. - Google Patents
A pharmaceutical composition for preventing or treating breast cancer containing a polymorph of tetraarsenic hexaoxide and a method for producing the same. Download PDFInfo
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- JP6824432B2 JP6824432B2 JP2019547058A JP2019547058A JP6824432B2 JP 6824432 B2 JP6824432 B2 JP 6824432B2 JP 2019547058 A JP2019547058 A JP 2019547058A JP 2019547058 A JP2019547058 A JP 2019547058A JP 6824432 B2 JP6824432 B2 JP 6824432B2
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- Prior art keywords
- breast cancer
- pharmaceutical composition
- tetraarsenic hexaoxide
- hexaoxide
- polymorph
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Description
本発明は、六酸化四砒素の結晶多形を含む乳癌予防または治療用薬学組成物に関するものである。 The present invention relates to a pharmaceutical composition for the prevention or treatment of breast cancer, which comprises a crystalline polymorph of tetraarsenic hexaoxide.
癌は制御されない細胞成長と特徴付けられ、このような異常な細胞成長により腫瘍（tumor）と呼ばれる細胞塊りが形成されて周囲の組織に侵入し、甚だしい場合には身体の他の器官に転移されることもある。学問的には新生物（neoplasia）とも呼ばれる。癌は多様な程度の有病率で身体の全ての組織及び臓器に影響を及ぼす。 Cancer is characterized by uncontrolled cell growth, and such abnormal cell growth forms a cell mass called a tumor that invades surrounding tissues and, in extreme cases, metastasizes to other organs in the body. It may be done. Academically, it is also called a neoplasm. Cancer affects all tissues and organs of the body with varying degrees of prevalence.
乳癌（breast cancer）は経済的成長に従う生活水準の向上、食生活の変化と西欧化、出産、及び授乳方法の変化などにより発生率が徐々に増加して女性腫瘍のうちの１位を占める（非特許文献１）。乳癌は***の中に留まる陽性腫瘍とは異なり、他の器官に広がって生命を威嚇することがある悪性腫瘍で、転移性乳癌から固形腫瘍まで非常に多様な生物学的特性を有しているので、多様な治療的選択と予後を有する。 Breast cancer is the number one female tumor with a gradual increase in incidence due to improved living standards following economic growth, changes in eating habits and westernization, childbirth, and changes in breastfeeding methods () Non-Patent Document 1). Breast cancer is a malignant tumor that can spread to other organs and be life-threatening, unlike positive tumors that remain in the breast, and has a wide variety of biological properties, from metastatic breast cancer to solid tumors. So it has a variety of therapeutic choices and prognosis.
最近、根治的切除術、坑癌化学療法、及びホルモン療法などの発展により乳癌の治療結果が相当に向上したことにもかかわらず、今までも腋窩リンパ節転移のない患者の約２５〜３０％で、腋窩リンパ節転移がある患者の約７５〜８０％で１０年内に再発しており、これらのうちの大部分は転移性乳癌により死亡している。たゆまぬ乳癌患者の増加によって転移性乳癌患者もやはり増加しているので、早期乳癌患者と共にこれら患者の治療方法、予後、これに影響を及ぼす因子に対する研究が持続しているが、まだ微小な実状である。 Approximately 25-30% of patients without axillary lymphadenopathy have been treated, despite recent advances in definitive resection, anticancer chemotherapy, and hormone therapy that have significantly improved breast cancer treatment outcomes. In about 75-80% of patients with axillary lymphadenopathy have relapsed within 10 years, most of whom die from metastatic breast cancer. As the number of patients with metastatic breast cancer is also increasing due to the constant increase in breast cancer patients, research on treatment methods, prognosis, and factors influencing these patients is ongoing along with patients with early-stage breast cancer, but the reality is still small. Is.
したがって、乳癌の治療と関連して乳癌の転移有無に関わらず、優れる坑癌効果を有する治療剤の開発が持続的に要求されている実状である。 Therefore, there is a continuous demand for the development of a therapeutic agent having an excellent anticancer effect regardless of the presence or absence of breast cancer metastasis in relation to the treatment of breast cancer.
一方、本発明者らは既に砒素が含まれた自然産信石から分離精製技術を通じて精製された六酸化四砒素が動物実験で癌転移抑制効果を示しており、併せて、子宮癌、膀胱癌、肺癌、上顎洞癌、腎臓癌などの末期癌患者に投与した時、優れる坑癌治療効果があるという技術的特徴として特許登録（特許文献１）を受けたことがある。 On the other hand, the present inventors have shown that tetraarsenic hexaoxide, which has already been purified from naturally occurring stones containing arsenic through separation and purification technology, has a cancer metastasis-suppressing effect in animal experiments, and also has uterine cancer and bladder cancer. , Has received patent registration (Patent Document 1) as a technical feature that it has an excellent anticancer therapeutic effect when administered to patients with terminal cancers such as lung cancer, maxillary sinus cancer, and kidney cancer.
本発明者らが砒素に対する持続的な研究結果、前記特許登録に開示された方法と異なる新規な製造方法により、六酸化四砒素の結晶多形ａが９９％以上である六酸化四砒素を製造することができ、このような六酸化四砒素を含む組成物が特に乳癌予防または治療に顕著な効果があることを明らかにして、本発明を完成するようになった。 As a result of continuous research on arsenic by the present inventors, tetraarsenic hexaoxide having a crystal polymorphism a of tetraarsenic hexaoxide of 99% or more is produced by a novel production method different from the method disclosed in the patent registration. The present invention has been completed by clarifying that such a composition containing tetraarsenic hexaoxide has a particularly remarkable effect on the prevention or treatment of breast cancer.
本発明の目的は、有効成分として六酸化四砒素（Ａｓ４Ｏ６）の結晶多形を含む乳癌予防または治療用薬学組成物を提供することにある。 An object of the present invention is to provide a pharmaceutical composition for preventing or treating breast cancer containing a crystalline polymorph of tetraarsenic hexaoxide (As 4 O 6 ) as an active ingredient.
本発明の他の目的は、有効成分として六酸化四砒素（Ａｓ４Ｏ６）の結晶多形を含む乳癌予防または治療用薬学組成物の製造方法を提供することにある。 Another object of the present invention is to provide a method for producing a pharmaceutical composition for preventing or treating breast cancer, which comprises a crystalline polymorph of tetraarsenic hexaoxide (As 4 O 6 ) as an active ingredient.
また、本発明の目的は有効成分として六酸化四砒素（Ａｓ４Ｏ６）の結晶多形を含む乳癌転移抑制用薬学組成物を提供することにある。 Another object of the present invention is to provide a pharmaceutical composition for suppressing breast cancer metastasis containing a polymorph of tetraarsenic hexaoxide (As 4 O 6 ) as an active ingredient.
本発明は有効成分に六酸化四砒素を含む乳癌予防または治療用薬学組成物であって、前記六酸化四砒素は六酸化四砒素結晶多形ａ（Ａｓ４Ｏ６−ａ）が９９％以上である乳癌予防または治療用組成物に関するものである。 The present invention is a pharmaceutical composition for preventing or treating breast cancer containing tetraarsenic hexaoxide as an active ingredient, and the tetraarsenic hexaoxide contains 99% or more of tetraarsenic hexaoxide crystal polymorph a (As 4 O 6 −a). It relates to a composition for preventing or treating breast cancer.
前記組成物の六酸化四砒素は塩化ナトリウムを１００〜８００℃に加熱した後、冷却する第１工程；塩化ナトリウムの上に三酸化二砒素（Ａｓ２Ｏ３）を上げた後、密閉状態で１００℃から１０００℃まで加熱した後、冷却する第２工程；昇華された砒素を捕集する濾過紙で結晶化された結晶を分離する第３工程；及び前記第３工程で得た結晶を第２工程の三酸化二砒素の代わりに使用して第２工程及び第３工程を４〜１０回繰り返して六酸化四砒素結晶を得る第４工程；を通じて製造できる。 The composition of arsenic trioxide is the first step of heating sodium chloride to 100 to 800 ° C. and then cooling it; arsenic trioxide (As 2 O 3 ) is raised on sodium chloride and then sealed. A second step of heating from 100 ° C. to 1000 ° C. and then cooling; a third step of separating crystals crystallized with a filter paper for collecting sublimated arsenic; and a third step of obtaining the crystals obtained in the third step. It can be produced through the fourth step; in which the second and third steps are repeated 4 to 10 times to obtain arsenic trioxide crystals, which is used instead of the two steps of arsenic trioxide.
前記組成物の六酸化四砒素は、六酸化四砒素の結晶多形ｂ（Ａｓ４Ｏ６−ｂ）が１％未満に含まれることができる。 The arsenic hexoxide compositions may be arsenic hexoxide polymorph b (As 4 O 6 -b) is contained in less than 1%.
前記六酸化四砒素は、純度が９９．９％以上でありうる。 The tetraarsenic hexaoxide can have a purity of 99.9% or higher.
前記Ａｓ４Ｏ６−ａ及びＡｓ４Ｏ６−ｂは以下の（i）乃至（iii）の特性を有するものでありうる： The As 4 O 6- a and As 4 O 6- b may have the following characteristics (i) to (iii):
前記Ａｓ４Ｏ６−ａはＸ−線粉末回折分光図で、光源波長が１．５４０６Åの時、回折角２θ １０°〜５０°範囲で、１°／ｍｉｎの速度（scan step ０．０２°）で表示されたピークが１３．８４、２７．８８、３２．３２、３５．３、３９．８４、４２．３８、４６．３４、４８．６、及び４９．３４と示されることを特徴とする結晶形である（図１参照）。また、２θ値１３．８と２７．９で示される主ピークの割合が１：１．３であることを特徴とする。 The As 4 O 6- a is an X-ray powder diffraction spectrometer, and when the light source wavelength is 1.5406 Å, the diffraction angle is 2θ in the range of 10 ° to 50 ° and the speed is 1 ° / min (scan step 0.02 °). ) Are shown as 13.84, 27.88, 32.32, 35.3, 39.84, 42.38, 46.34, 48.6, and 49.34. It is a crystalline form (see FIG. 1). Further, the ratio of the main peaks represented by the 2θ values 13.8 and 27.9 is 1: 1.3.
前記Ａｓ４Ｏ６−ｂはＸ−線粉末回折分光図で、光源波長が１．５４０６Åの時、回折角２θ １０°〜５０°範囲で１°／ｍｉｎの速度（scan step ０．０２°）で表示されたピークが１３．８６、２７．９２、３２．３６、３５．３４、３９．９、４２．４４、４６．４、４８．６６、及び４９．４と示されることを特徴とする結晶形である（図１参照）。また、２θ値１３．８と２７．９で示される主ピークの割合が１：２．５であることを特徴とする。
The As 4 O 6- b is an X-ray powder diffraction spectrometer, and when the light source wavelength is 1.5406 Å, the speed is 1 ° / min in the diffraction angle range of
本発明の他の態様によれば、有効成分に六酸化四砒素を含む乳癌転移抑制用薬学組成物であって、前記六酸化四砒素は六酸化四砒素結晶多形ａ（Ａｓ４Ｏ６−ａ）が９９％以上である乳癌転移抑制用薬学組成物に関するものである。 According to another aspect of the present invention, the pharmaceutical composition for suppressing breast cancer metastasis containing tetraarsenic hexaoxide as an active ingredient, wherein the tetraarsenic hexaoxide is a polymorph of tetraarsenic hexaoxide crystal a (As 4 O 6 −). It relates to a pharmaceutical composition for suppressing breast cancer metastasis in which a) is 99% or more.
以下、本発明をより詳細に説明する。 Hereinafter, the present invention will be described in more detail.
本発明は有効成分として六酸化四砒素（Ａｓ４Ｏ６）を含む乳癌予防または治療用薬学組成物であって、前記六酸化四砒素は六酸化四砒素の結晶多形ａ（Ａｓ４Ｏ６−ａ）が９９％以上である薬学組成物に関するものである。 The present invention is a pharmaceutical composition for preventing or treating breast cancer containing tetraarsenic hexaoxide (As 4 O 6 ) as an active ingredient, wherein the tetraarsenic hexaoxide is a crystalline polymorph a (As 4 O 6) of tetraarsenic hexaoxide. -A) relates to a pharmaceutical composition having a content of 99% or more.
本発明の他の態様によれば、有効成分として六酸化四砒素（Ａｓ４Ｏ６）の結晶多形を含む乳癌予防または治療用薬学組成物の製造方法であって、塩化ナトリウムを１００〜８００℃に加熱した後、冷却する第１工程；塩化ナトリウムの上に三酸化二砒素（Ａｓ２Ｏ３）を上げた後、密閉状態で１００℃から１０００℃まで加熱した後、冷却する第２工程；昇華された砒素を捕集する濾過紙で結晶化された結晶を分離する第３工程；及び前記第３工程で得た結晶を第２工程の三酸化二砒素の代わりに使用して第２工程及び第３工程を４〜１０回繰り返して六酸化四砒素結晶を得る第４工程；を含む方法により製造され、前記第４工程で得た六酸化四砒素結晶が六酸化四砒素の結晶多形ａ（Ａｓ４Ｏ６−ａ）を９９％以上含むことを特徴とする乳癌予防または治療用薬学組成物の製造方法に関するものである。
According to another aspect of the present invention, there is a method for producing a pharmaceutical composition for preventing or treating breast cancer, which comprises a crystalline polyform of arsenic trioxide (As 4 O 6 ) as an active ingredient, wherein sodium chloride is 100 to 800. First step of heating to ° C and then cooling; second step of raising arsenic trioxide (As 2 O 3 ) on sodium chloride, heating from 100 ° C to 1000 ° C in a sealed state, and then cooling. The third step of separating the crystals crystallized with a filter paper that collects the sublimated arsenic; and the second step of using the crystals obtained in the third step instead of the arsenic trioxide in the second step. It is produced by a method including the fourth step of obtaining arsenic trioxide crystals by repeating the steps and the
高嶺土材質の合成反応器、及び合成反応器の上部にフィルターが装着できるクランプを準備し、合成反応器内に塩化ナトリウムをあげて加熱及び冷却を進行する。本発明の製造方法で塩化ナトリウムを使用する理由は、第２工程で三酸化二砒素を塩化ナトリウムの上にあげて加熱することによって、砒素化合物に熱が均等に伝達されながら砒素化合物が昇華することに助けになるためであり、第１工程を通じてこのような塩化ナトリウムの不純物及び水分を除去するために１００〜８００℃に２〜６時間の間加熱する。第１工程において、塩化ナトリウムを加熱した後、室温で３〜１０時間の間冷却する。 Prepare a synthetic reactor made of high-lying soil material and a clamp on which a filter can be attached on top of the synthetic reactor, and raise sodium chloride in the synthetic reactor to proceed with heating and cooling. The reason for using sodium chloride in the production method of the present invention is that by raising diarsenic trioxide on sodium chloride and heating it in the second step, the arsenic compound is sublimated while heat is evenly transferred to the arsenic compound. Especially to help, heating to 100-800 ° C. for 2-6 hours to remove such impurities and water content of sodium chloride throughout the first step. In the first step, sodium chloride is heated and then cooled at room temperature for 3-10 hours.
次に、塩化ナトリウムの上に三酸化二砒素（Ａｓ２Ｏ３）を上げた後、密閉状態で１００℃から１０００℃まで加熱し、以後、冷却する第２工程を進行する。ここで、三酸化二砒素を上げた後、クランプに昇華される砒素が捕集できるフィルター（濾過紙）を各フィルターとフィルターとの間の間隔が２ｍｍ〜６ｍｍになるように３〜６個装着する。この時に使われるフィルターは、平量（basic weight）７０〜１００ｇ／ｍ２、厚さ（thickness）０．１７〜０．２５ｍｍ、濾過速度（filtration speed）２２〜３０ｓ／１００ｍｌ、及び保留粒子径（retention rate）５〜１０μｍのものを使用することが好ましい。 Next, after raising arsenic trioxide (As 2 O 3 ) on sodium chloride, it is heated from 100 ° C. to 1000 ° C. in a closed state, and then the second step of cooling is carried out. Here, after raising arsenic trioxide, attach 3 to 6 filters (filter paper) that can collect arsenic sublimated to the clamp so that the distance between each filter is 2 mm to 6 mm. To do. The filters used at this time are a basic weight of 70 to 100 g / m 2 , a thickness of 0.17 to 0.25 mm, a filtration speed of 22 to 30 s / 100 ml, and a retention particle size (retention particle size). It is preferable to use a retention rate of 5 to 10 μm.
フィルターを装着してから密閉させた後、合成反応器の下部に１００℃から１０００℃まで段階的に上げながら３時間〜１０時間の間加熱して濾過紙の最上部の中心部の温度は１５０℃±１００℃維持されるようにし、濾過紙を通過しながら六酸化四砒素が結晶化されるようにする。そして、常温で５時間以上、好ましくは５時間〜１０時間の間冷却する。 After installing the filter and sealing it, heat it to the bottom of the synthetic reactor in stages from 100 ° C to 1000 ° C for 3 to 10 hours, and the temperature of the center of the top of the filter paper is 150. The temperature is maintained at ± 100 ° C., and tetraarsenic hexaoxide is crystallized while passing through the filter paper. Then, it is cooled at room temperature for 5 hours or more, preferably 5 hours to 10 hours.
次に、離隔して積層に設置された３〜６個の濾過紙に捕集された白色結晶を分離する第３工程を遂行する。 Next, a third step of separating the white crystals collected on 3 to 6 filter papers separately placed in the laminate is performed.
合成反応器の塩化ナトリウムの上に残留する微量の三酸化二砒素を除去した後、前記捕集された白色結晶を上げた後、第２工程及び第３工程を同一条件で４〜１０回繰り返して最終的に六酸化四砒素結晶を収得する。本発明の製造方法により得られた結晶構造を確認した結果、大部分Ａｓ４Ｏ６−ａであり、Ａｓ４Ｏ６−ａが９９％以上であると確認された。 After removing a small amount of arsenic trioxide remaining on the sodium chloride of the synthetic reactor, the collected white crystals are raised, and then the second and third steps are repeated 4 to 10 times under the same conditions. Finally, arsenic hexaoxide crystals are obtained. As a result of confirming the crystal structure obtained by the production method of the present invention, it was confirmed that most of them were As 4 O 6- a and that As 4 O 6- a was 99% or more.
本発明の六酸化四砒素の結晶多形を含む薬学組成物は、乳癌予防または治療及び乳癌転移抑制に有用に使用できる。 The pharmaceutical composition containing a crystalline polymorph of tetraarsenic hexaoxide of the present invention can be usefully used for breast cancer prevention or treatment and suppression of breast cancer metastasis.
本発明の薬学組成物は各々通常の方法によって、散剤、顆粒剤、錠剤、カプセル剤、懸濁液、エマルジョン、シロップ、エアゾールなどの経口型剤形、外用剤、坐剤、及び滅菌注射溶液の形態に剤形化して使用できる。前記薬学組成物に含まれることができる担体、賦形剤、及び希釈剤には、ラクトース、デキストロース、スクロース、ソルビトール、マンニトール、キシリトール、エリスリトール、マルチトール、澱粉、アカシアゴム、アルジネート、ゼラチン、カルシウムホスフェート、カルシウムシリケート、セルロース、メチルセルロース、非晶質セルロース、ポリビニルピロリドン、水、メチルヒドロキシ安息香酸、プロピルヒドロキシ安息香酸、タルク、マグネシウムステアレート、及び鉱物油を挙げることができる。製剤化する場合には、普通使用する充填剤、増量剤、結合剤、湿潤剤、崩解剤、界面活性剤などの希釈剤、または賦形剤を使用して調剤される。経口投与のための固形製剤には、錠剤、丸剤、散剤、顆粒剤、カプセル剤などが含まれて、このような固形製剤は本発明の六酸化四砒素に少なくとも１つ以上の賦形剤、例えば、澱粉、炭酸カルシウム、スクロースまたはラクトース、ゼラチンなどを混ぜて調剤される。また、単純な賦形剤の以外にマグネシウムステアレート、タルクのような潤滑剤も使われる。経口のための液状製剤には、懸濁剤、内用液剤、油剤、シロップ剤などが該当されるが、よく使われる単純希釈剤である水、リキッドパラフィンの以外にさまざまな賦形剤、例えば、湿潤剤、甘味剤、芳香剤、保存剤などが含まれることができる。非経口投与のための製剤には滅菌された水溶液、非水性溶剤、懸濁剤、油剤、凍結乾燥製剤、坐剤が含まれる。非水性溶剤、懸濁剤には、プロピレングリコール、ポリエチレングリコール、オリーブオイルのような植物性油、エチルオレートのような注射可能なエステルなどが使用できる。坐剤の基剤には、ウィテップゾール（witepsol）、マクロゴール、ツイーン（tween）６１、カカオ脂、ラウリン脂、グリセロゼラチンなどが使用できる。 The pharmaceutical compositions of the present invention can be prepared by ordinary methods for powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and other oral dosage forms, external preparations, suppositories, and sterile injection solutions. It can be used as a dosage form. Carriers, excipients, and diluents that can be included in the pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, martitol, starch, acacia gum, alginate, gelatin, calcium phosphate. , Calcium silicate, cellulose, methyl cellulose, amorphous cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoic acid, propyl hydroxybenzoic acid, talc, magnesium stearate, and mineral oil. In the case of formulation, it is prepared using commonly used fillers, bulking agents, binders, wetting agents, disrupting agents, diluents such as surfactants, or excipients. Solid preparations for oral administration include tablets, pills, powders, granules, capsules and the like, such solid preparations being at least one excipient for the sucrose hexaoxide of the present invention. , For example, starch, calcium carbonate, sucrose or lactose, gelatin and the like are mixed and prepared. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral use include suspensions, liquids for internal use, oils, syrups, etc., but various excipients other than the commonly used simple diluents water and liquid paraffin, such as liquid paraffin, are used. , Wetting agents, sweeteners, fragrances, preservatives, etc. can be included. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, oils, lyophilized preparations, suppositories. As the non-aqueous solvent and suspension, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable esters such as ethyl oleate can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, lauric acid, glycerogelatin and the like can be used.
前記薬学組成物の投与量は治療を受ける対象の年齢、性別、体重と、治療する特定疾患または病理状態、疾患または病理状態の深刻度、投与経路及び処方者の判断によって変わる。このような因子に基づいた投与量の決定は当業者の水準内にあり、一般的に投与量は０．０１ｍｇ／ｋｇ／日乃至略５００ｍｇ／ｋｇ／日の範囲である。より好ましい投与量は０．１ｍｇ／ｋｇ／日乃至１００ｍｇ／ｋｇ／日である。投与は１日に１回投与することもでき、数回に分けて投与することもできる。前記投与量はどんな面でも本発明の範囲を限定するものではない。 The dose of the pharmaceutical composition depends on the age, sex, and body weight of the subject to be treated, the specific disease or pathological condition to be treated, the severity of the disease or pathological condition, the route of administration, and the judgment of the prescriber. Dosage determination based on such factors is within the standards of those skilled in the art, and doses generally range from 0.01 mg / kg / day to approximately 500 mg / kg / day. A more preferred dose is 0.1 mg / kg / day to 100 mg / kg / day. The administration can be administered once a day or in several divided doses. The dosage does not limit the scope of the invention in any way.
前記薬学組成物は、ネズミ、家畜、ヒトなどの哺乳動物に多様な経路に投与できる。投与の全ての方式は予想できるが、例えば、経口、直腸または静脈、筋肉、皮下、子宮内粘膜、または脳血管内注射により投与できる。 The pharmaceutical composition can be administered to mammals such as mice, livestock and humans by various routes. All methods of administration are predictable, but can be administered, for example, by oral, rectal or venous, muscular, subcutaneous, intrauterine mucosa, or cerebrovascular injection.
本発明の乳癌予防または治療用薬学組成物は、六酸化四砒素の結晶多形ａが９９％以上である六酸化四砒素を含むことによって、優れる坑癌効果を有する。
また、本発明の薬学組成物は、乳癌転移を抑制する効果に優れることが確認された。
The pharmaceutical composition for preventing or treating breast cancer of the present invention has an excellent anticancer effect by containing tetraarsenic hexaoxide having a crystal polymorph a of 99% or more of tetraarsenic hexaoxide.
Further, it was confirmed that the pharmaceutical composition of the present invention is excellent in the effect of suppressing breast cancer metastasis.
以下、本発明の好ましい実施例を詳細に説明する。しかしながら、本発明はここで説明される実施例に限定されず、他の形態に具体化されることもできる。むしろ、ここで紹介される内容が徹底し完全になり、当業者に本発明の思想を十分に伝達するために提供するものである。 Hereinafter, preferred embodiments of the present invention will be described in detail. However, the present invention is not limited to the examples described herein, and can be embodied in other embodiments. Rather, the content introduced here is to be thoroughly and completely provided to those skilled in the art in order to fully convey the ideas of the present invention.
実施例１：本発明の六酸化四砒素の製造 Example 1: Production of tetraarsenic hexaoxide of the present invention
高嶺土で特殊製作された合成反応器（高さ１００ｍｍ、直径１９０ｍｍ）と、３〜６個のフィルターを装着することができるクランプを準備する。クランプは合成反応器から５０ｍｍ離れて１次クランプを設置し、前記１次クランプから２〜６ｍｍ間隔でその上部に２次〜６次クランプを設置し、この際、各クランプの規格は直径２１０ｍｍ及び厚さ１０ｍｍである。
Prepare a synthetic reactor (
称量した太い塩（水分含有量１０％以下）４００ｇ〜６００ｇを合成反応器に投入して２０ｍｍ内外に厚さを均等に押し固めて１００℃〜８００℃で３時間の間熱を徐々に加熱しながら反応器の内部の塩表面温度が２９０±３０℃になるように連続加熱して水分及び不純物を除去し、室温で５時間の間冷却させる。
Add 400 g to 600 g of the nominal amount of thick salt (
原料物質であるＡｓ２Ｏ３（純度９８％以上、製造社YUNNAN WENSHAN JINCHI ARSENIC CO., LTD.）１００ｇを合成反応器内の太い塩の上に入れて、合成機の上部に位置した昇華される砒素が捕集できるフィルター（濾過紙）を各フィルターとフィルターとの間の間隔が２〜６ｍｍになるように３〜６個のクランプを装着する。この時に使われるフィルターは、平量（basic weight）７０〜１００ｇ／ｍ２、厚さ（thickness）０．１７〜０．２５ｍｍ、濾過速度（filtration speed）２２〜３０ｓ／１００ｍｌ、及び保留粒子径（retention rate）５〜１０μｍのものを使用することが好ましい。 100 g of the raw material As 2 O 3 (purity 98% or more, manufacturer YUNNAN WENSHAN JINCHI ARSENIC CO., LTD.) Is placed on the thick salt in the synthetic reactor and sublimated located at the top of the synthesizer. Attach 3 to 6 clamps to the filter (filter paper) that can collect arsenic so that the distance between each filter is 2 to 6 mm. The filters used at this time are a basic weight of 70 to 100 g / m 2 , a thickness of 0.17 to 0.25 mm, a filtration speed of 22 to 30 s / 100 ml, and a retention particle size (retention particle size). It is preferable to use a retention rate of 5 to 10 μm.
クランプを用いてフィルターを固定させ、合成反応器の下部に熱を加えて１００℃から１，０００℃まで段階的に温度を上げる。まず合成反応器下部の外部温度を３５０℃±１００℃位になるように１時間の間加熱し、以後に合成反応器の下部の外部温度を６００〜６５０℃、及び７００〜１，０００℃位になるように加熱して、総５時間〜１０時間の間加熱してフィルターの最上部の濾過紙の中心部の温度が１５０℃±１００℃を維持するようにした後、常温で５〜７時間位冷却する。この過程で、合成反応器の塩の上に上がっている粉末Ａｓ２Ｏ３は合成反応器の内部で気体に変わって上昇してから、合成反応器の外部の上部温度が相対的に低いので、液体に変わり、以後、固体に結晶化されてフィルター上に白色結晶体が生成される。 The filter is fixed using a clamp, and heat is applied to the lower part of the synthetic reactor to gradually raise the temperature from 100 ° C. to 1,000 ° C. First, the external temperature of the lower part of the synthetic reactor is heated to about 350 ° C ± 100 ° C for 1 hour, and then the external temperature of the lower part of the synthetic reactor is about 600 to 650 ° C and 700 to 1,000 ° C. After heating for a total of 5 to 10 hours so that the temperature of the center of the filter paper at the top of the filter is maintained at 150 ° C ± 100 ° C, the temperature is 5 to 7 at room temperature. Cool for about an hour. In this process, the powder As 2 O 3 rising on the salt of the synthetic reactor turns into a gas inside the synthetic reactor and rises, and then the upper temperature outside the synthetic reactor is relatively low. , Turns into a liquid, and then crystallizes into a solid to produce white crystals on the filter.
採取した白色結晶体を合成反応器の太い塩の上に入れて、また加熱及び冷却し、結晶を採取する工程をまた４回繰り返して最終的に結晶１２．０ｇを得た。得られた砒素化合物の結晶の構造を確認した結果、大部分Ａｓ４Ｏ６−ａであり、Ａｓ４Ｏ６−ａが９９重量％以上であり、Ａｓ４Ｏ６−ｂが１重量％未満であると確認された。 The collected white crystals were placed on a thick salt of a synthetic reactor, heated and cooled, and the process of collecting crystals was repeated four times to finally obtain 12.0 g of crystals. As a result of confirming the crystal structure of the obtained arsenic compound, most of them were As 4 O 6- a, As 4 O 6- a was 99% by weight or more, and As 4 O 6- b was less than 1% by weight. It was confirmed that.
ＤＳＣ（示差走査熱分析）値が昇温速度が１０℃／ｍｉｎの時、Ａｓ４Ｏ６−ａは２８２．６７℃である点で吸熱ピーク（融点）が示されることが確認されており、Ａｓ４Ｏ６−ｂは２８６．７７℃である点で吸熱ピーク（融点）が示されることが確認された。 It has been confirmed that when the DSC (Differential Scanning Thermal Analysis) value is 10 ° C./min, the endothermic peak (melting point) is shown at the point where As 4 O 6- a is 282.67 ° C. It was confirmed that As 4 O 6- b showed an endothermic peak (melting point) at 286.77 ° C.
Ａｓ４Ｏ６−ａ及びＡｓ４Ｏ６−ｂの粉末Ｘ線回折分光図を図１に図示し、Ａｓ４Ｏ６−ａ及びＡｓ４Ｏ６−ｂの回折データは次の表２の通りである。 As As 4 O 6 -a and As 4 O 6 powder X-ray diffraction spectroscopy view of -b shown in FIG. 1, As 4 O 6 -a and As 4 O 6 diffraction data -b following table 2 Is.
図１及び表２から確認できるように、Ａｓ４Ｏ６−ａは２θ値１３．８と２７．９で示される主ピークの割合が１：１．３であり、Ａｓ４Ｏ６−ｂは２θ値１３．８と２７．９で示される主ピークの割合が１：２．５であることを特徴とする。製造された化合物のＤＳＣ分析、構造結晶、及びＸ線回折分析は、次のような方法により遂行した。 As can be confirmed from FIG. 1 and Table 2, As 4 O 6 −a has a ratio of the main peaks indicated by 2θ values of 13.8 and 27.9 of 1: 1.3, and As 4 O 6 −b is The ratio of the main peaks represented by the 2θ values of 13.8 and 27.9 is 1: 2.5. DSC analysis, structural crystal, and X-ray diffraction analysis of the produced compound were carried out by the following methods.
（１）ＤＳＣ分析 (1) DSC analysis
ＤＳＣ装備（SDT Q600 V20.9 Build 20）で、Ｎ２ １００ｍＬ／ｍｉｎを流しながら１０℃／ｍｉｎ昇温速度で３１０℃まで上昇させながら試料２０．０ｍｇを分析した。
With DSC equipment (SDT Q600 V20.9 Build 20), 20.0 mg of sample was analyzed while flowing
（２）Ｘ線結晶学 (2) X-ray crystallography
六酸化四砒素（Ａｓ４Ｏ６、ＭＷ＝３９５．６）の単結晶をglass fiberの上に上げた後、X-ray beamを照射して回折されて出る写真紋と回折データの体系性の有無を観察して空間群（space group）を決定し、単位格子定数（cell parameter）を決定する。回折強さは１０゜＜２θ＜５０゜範囲で収集する。このデータを構造結晶プログラム（ＳＨＥＬＸＴＬプログラム）を使用して重原子方法（Patterson方法）によりＡｓ４Ｏ６の結晶構造を確認する。 After raising a single crystal of tetraarsenic hexaoxide (As 4 O 6 , MW = 395.6) on a glass fiber, it is irradiated with an X-ray beam and diffracted to produce a systematic photographic pattern and diffraction data. Observe the presence or absence to determine the space group, and determine the unit lattice constant (cell parameter). Diffraction intensity is collected in the range of 10 ° <2θ <50 °. The crystal structure of As 4 O 6 is confirmed by the heavy atom method (Patterson method) using this data using the structural crystal program (SHELXTL program).
（３）Ｘ線回折分析法 (3) X-ray diffraction analysis method
収得した結晶を粉砕して１０μｍ〜３０μｍ（−３２５メッシュ）の粒子に作り、Ｘ−線回折分析用ガラスホルダー（２０ｍｍ×１６ｍｍ×１ｍｍ）に充填させた後、ガラススライドなどで圧着させ、検体面とホルダー面が平行になるように滑らかにして試料を準備した。ＸＲＤのＣｕ Ｋα１（１．５４０６０Å）を用いて２θ １０°〜５０°範囲で１°／ｍｉｎの速度（scan step ０．０２°）で結晶のＸ−線回折分光図を描く。 The obtained crystals are crushed into particles of 10 μm to 30 μm (-325 mesh), filled in a glass holder for X-ray diffraction analysis (20 mm × 16 mm × 1 mm), and then crimped with a glass slide or the like to obtain a sample surface. The sample was prepared by smoothing the holder surface so that it was parallel to each other. Using XRD Cu Kα 1 (1.54060 Å), an X-ray diffraction spectroscopy of the crystal is drawn in the range of 2θ 10 ° to 50 ° at a rate of 1 ° / min (scan step 0.02 °).
比較例１：六酸化四砒素の製造 Comparative Example 1: Production of tetraarsenic hexaoxide
高嶺土で特殊製作された合成反応器（高さ１００ｍｍ、直径１９０ｍｍ）と、３〜６個のフィルターが装着できるクランプを準備する。クランプは合成反応器から５０ｍｍ離れて１次クランプを設置し、前記１次クランプから２〜６ｍｍ間隔でその上部に２次〜６次クランプを設置し、この時の各クランプの規格は直径２１０ｍｍ及び厚さ１０ｍｍである。
Prepare a synthetic reactor (
称量した太い塩（水分含有量１０％以下）４００ｇ〜６００ｇを合成反応器に投入して２０ｍｍ内外に厚さを均等に押し固めて１００℃〜８００℃３時間の間熱を徐々に加熱しながら反応器の内部の塩表面温度が２９０±３０℃になるように連続加熱して水分及び不純物を除去し、室温で５時間の間冷却させる。
400 g to 600 g of the nominal amount of thick salt (
原料物質であるＡｓ２Ｏ３（純度９８％以上、製造社YUNNAN WENSHAN JINCHI ARSENIC CO., LTD.）１００ｇを合成反応器内の太い塩の上に入れて、合成機の上部に位置した昇華される砒素が捕集できるフィルター（濾過紙）を各フィルターとフィルターとの間の間隔が２〜６ｍｍになるように３〜６個のクランプを装着する。この時に使われるフィルターは、平量（basic weight）７０〜１００ｇ／ｍ２、厚さ（thickness）０．１７〜０．２５ｍｍ、濾過速度（filtration speed）２２〜３０ｓ／１００ｍｌ、及び保留粒子径（retention rate）５〜１０μｍのものを使用することが好ましい。 100 g of the raw material As 2 O 3 (purity 98% or more, manufacturer YUNNAN WENSHAN JINCHI ARSENIC CO., LTD.) Is placed on the thick salt in the synthetic reactor and sublimated located at the top of the synthesizer. Attach 3 to 6 clamps to the filter (filter paper) that can collect arsenic so that the distance between each filter is 2 to 6 mm. The filters used at this time are a basic weight of 70 to 100 g / m 2 , a thickness of 0.17 to 0.25 mm, a filtration speed of 22 to 30 s / 100 ml, and a retention particle size (retention particle size). It is preferable to use a retention rate of 5 to 10 μm.
クランプを用いてフィルターを固定させ、合成反応器の下部に熱を加えて１００℃から１，０００℃まで段階的に温度を上げる。まず、合成反応器の下部の外部温度を３５０℃±１００℃位になるように１時間の間加熱し、以後に合成反応器の下部の外部温度を６００〜６５０℃、及び７００〜１，０００℃位になるように加熱して、総５時間〜１０時間の間加熱してフィルターの最上部の濾過紙の中心部の温度が１５０℃±１００℃を維持するようにした後、常温で５〜７時間位冷却する。この過程で、合成反応器の塩の上に上げている粉末Ａｓ２Ｏ３は合成反応器の内部で気体に変わって上昇してから、合成反応器の外部の上部温度が相対的に低いので液体に変わり、以後、固体に結晶化されてフィルター上に白色結晶体が生成される。フィルターから４８．５ｇの結晶を採取した。採取した砒素化合物の結晶構造を確認した結果、９９％以上が大部分Ａｓ４Ｏ６−ｂであると確認された。
The filter is fixed using a clamp, and heat is applied to the lower part of the synthetic reactor to gradually raise the temperature from 100 ° C. to 1,000 ° C. First, the external temperature of the lower part of the synthetic reactor is heated to about 350 ° C. ± 100 ° C. for 1 hour, and then the external temperature of the lower part of the synthetic reactor is 600 to 650 ° C. and 700 to 1,000. Heat to around ° C and heat for a total of 5 to 10 hours to maintain the temperature of the center of the filter paper at the top of the filter at 150 ° C ± 100 ° C, and then at
比較例２乃至４：六酸化四砒素の製造 Comparative Examples 2 to 4: Production of tetraarsenic hexaoxide
実施例１（結晶多形Ａｓ４Ｏ６−ａが９９％以上である組成物）と比較例１（結晶多形Ａｓ４Ｏ６−ｂが９９％以上である組成物）を各々４：１、及び１：１に混合して、各々比較例２及び比較例３にした。 Example 1 (composition in which polymorphic As 4 O 6- a is 99% or more) and Comparative Example 1 (composition in which polymorphic As 4 O 6- b is 99% or more) are 4: 1 respectively. , And 1: 1 were mixed to make Comparative Example 2 and Comparative Example 3, respectively.
実験例１：ヒト乳癌（human breast cancer）細胞増殖抑制効果実験 Experimental example 1: Human breast cancer Cell growth inhibitory effect experiment
（１）実験材料及び細胞培養 (1) Experimental materials and cell culture
牛胎兒血清（ＦＢＳ）と細胞培養培地を準備し（Hyclone社）、ジメチルスルホキシド（ＤＭＳＯ）、３−（４，５−ジメチル−チアゾール−２イル）−２，５−ジフェニルテトラゾリウムブロマイド（３−（４，５−dimetyl-thiazol-2yl）−２，５−diphenyltetrazolium bromide、ＭＴＴ）を準備した（Amresco LLC、ＵＳＣ）。 Prepare fetal bovine serum (FBS) and cell culture medium (Hyclone), dimethyl sulfoxide (DMSO), 3- (4,5-dimethyl-thiazole-2yl) -2,5-diphenyltetrazolium bromide (3-( 4,5-dimetyl-thiazol-2yl) -2,5-diphenyltetrazolium bromide (MTT) was prepared (Amresco LLC, USC).
ヒトの癌細胞株であって、ヒト乳癌細胞株（human breast cancer cells）であるＭＣＦ−７細胞及びＳＫ−ＢＲ−３細胞を中国科学アカデミーの上海細胞銀行から分譲を受けて、ＭＣＦ−７細胞は１０％ ＦＢＳ、１００Ｕ／ｍＬペニシリン、及び１００μｇ／ｍＬストレプトマイシンが含まれたＭＥＭ（Minimum Essential Media）培地を、ＳＫ−ＢＲ−３細胞は１０％ＦＢＳ、１００Ｕ／ｍＬペニシリン、及び１００μｇ／ｍＬストレプトマイシンが含まれたＤＭＥＭ（Dulbecco’s modified Eagle’s medium）培地を用いて５％ＣＯ２及び９５％空気と湿気がある状態の培養器で細胞を培養した。培地は３日毎に交替した。 MCF-7 cells and SK-BR-3 cells, which are human breast cancer cell lines, were sold from Shanghai Cell Bank of the Chinese Academy of Sciences and MCF-7 cells. Is MEM (Minimum Essential Media) medium containing 10% FBS, 100 U / mL penicillin, and 100 μg / mL streptomycin, and SK-BR-3 cells are 10% FBS, 100 U / mL penicillin, and 100 μg / mL streptomycin. Cells were cultured in an incubator with 5% CO 2 and 95% air and moisture using the included DMEM (Dulbecco's modified Eagle's medium) medium. The medium was changed every 3 days.
（２）細胞増殖アッセイ（ＭＴＴアッセイ） (2) Cell proliferation assay (MTT assay)
実施例１、及び比較例１乃至３の細胞増殖に対する効果をＭＴＴアッセイを用いて評価した。ＭＴＴアッセイはＭＴＴに対して生きている細胞が不溶性暗青色ホルマザン反応物を生成する能力に基盤する。トリプシンを処理して細胞を培地に浮遊させて集めた後、４×１０３細胞／ウェル（cells／well）の密度で９６−ウェル培養ディッシュ（Costar、Cambridge、ＭＡ、ＵＳＡ）に分株される。２４時間後に、実施例１、及び比較例１乃至３の各々を０、０．６２５、１．２５、２．５、５、１０、２０、４０、または８０μMになるように１０％のＦＢＳを含む培地が入っている細胞に処理して培養した。この際、実施例１、及び比較例１乃至３は、１Ｍ水酸化ナトリウムに５×１０−２Ｍ濃度で溶解させた貯蔵溶液を用いた。細胞増殖に対するＭＴＴアッセイを遂行するために、試料処理後、４８時間及び７２時間の間培養した細胞から上澄液を除去し、ウェル（well）当たり５ｍｇ／ｍＬのＭＴＴ溶液を２０μＬずつ添加してから、ホルマザン結晶を形成するために３７℃で４時間の間インキュベーションした。インキュベーション後に、上澄液をまた除去し、ＤＭＳＯを全てのウェル当たり１００μＬずつ添加し、暗青色結晶を完全に溶解するように混合した。室温で１５分間放置して全ての結晶が完全に溶解されるようにし、５７０ｎｍ（Ａ５７０ｎｍ）波長でマイクロ−プレート機で吸光度を測定した。 The effects of Example 1 and Comparative Examples 1 to 3 on cell proliferation were evaluated using the MTT assay. The MTT assay is based on the ability of living cells to produce an insoluble dark blue formazan reactant to MTT. After trypsin treatment and cells are suspended and collected in medium, they are split into 96-well culture dishes (Costar, Cambridge, MA, USA) at a density of 4 × 10 3 cells / well (cells / well). .. After 24 hours, each of Example 1 and Comparative Examples 1 to 3 was subjected to 10% FBS to 0, 0.625, 1.25, 2.5, 5, 10, 20, 40, or 80 μM. The cells containing the containing medium were treated and cultured. At this time, in Example 1 and Comparative Examples 1 to 3, a storage solution dissolved in 1 M sodium hydroxide at a concentration of 5 × 10 −2 M was used. To carry out the MTT assay for cell proliferation, after sample processing, the supernatant was removed from the cells cultured for 48 and 72 hours, and 20 μL of 5 mg / mL MTT solution was added per well. Incubated at 37 ° C. for 4 hours to form formazan crystals. After incubation, the supernatant was also removed and DMSO was added in 100 μL per all wells and mixed to completely dissolve the dark blue crystals. Absorbance was measured with a micro-plate machine at a wavelength of 570 nm (A 570 nm ) so that all crystals were completely dissolved by leaving at room temperature for 15 minutes.
（３）統計分析 (3) Statistical analysis
試料を処理しない対照群の吸光度値を１００として計算し、前記対照群対比試料を処理した処理群の吸光度値を較正（calibration）し、細胞増殖抑制率を以下の式によって計算した。 The absorbance value of the control group not treated with the sample was calculated as 100, the absorbance value of the treated group treated with the control group comparison sample was calibrated, and the cell growth inhibition rate was calculated by the following formula.
細胞増殖抑制率（％）＝（（対照群細胞の平均吸光度−処理群細胞の Cell growth inhibition rate (%) = ((Average absorbance of control group cells-of treated group cells
平均吸光度）／対照群細胞の平均吸光度）×１００ Average absorbance) / Average absorbance of control group cells) x 100
全てのデータは平均±標準誤差（means±ＳＥＭ）で表現される。１元配置分散分析（one-way analysis of variance、ＡＮＯＶＡ）後、ダネットの事後検証（Dunnett’s post-test）により多重比較を遂行した。留意水準はｐ＜０．０５であり、各実験は３回ずつ反復された。 All data are expressed as mean ± standard error (means ± SEM). After one-way analysis of variance (ANOVA), multiple comparisons were performed by Dunnett's post-test. The level of attention was p <0.05, and each experiment was repeated 3 times.
（４）ＭＣＦ−７細胞利用結果 (4) Results of MCF-7 cell utilization
実施例１、及び比較例１乃至３をヒト乳癌細胞株であるＭＣＦ−７細胞に処理してから、４８時間及び７２時間培養し、ＭＴＴアッセイを遂行した結果を図２に示した。実施例１を処理した後、４８時間（図２Ａ）及び７２時間（図２Ｂ）培養した実験結果全てで、比較例１を処理した場合に比べて乳癌細胞株であるＭＣＦ−７細胞の増殖抑制率の高いことが確認された。また、実施例１と比較例１が４：１に混合された比較例２や、１：１に混合された比較例３に比べて、ＭＣＦ−７細胞の増殖抑制率の高いことが確認された。 The results of performing the MTT assay after treating Example 1 and Comparative Examples 1 to 3 into MCF-7 cells, which are human breast cancer cell lines, and culturing for 48 hours and 72 hours are shown in FIG. In all the experimental results of culturing for 48 hours (FIG. 2A) and 72 hours (FIG. 2B) after treating Example 1, the growth of MCF-7 cells, which is a breast cancer cell line, was suppressed as compared with the case of treating Comparative Example 1. It was confirmed that the rate was high. Further, it was confirmed that the growth inhibition rate of MCF-7 cells was higher than that of Comparative Example 2 in which Example 1 and Comparative Example 1 were mixed 4: 1 and Comparative Example 3 in which Comparative Example 1 was mixed 1: 1. It was.
（５）ＳＫ−ＢＲ−３細胞利用結果 (5) Results of SK-BR-3 cell utilization
実施例１、及び比較例１乃至３をヒト乳癌細胞株であるＳＫ−ＢＲ−３細胞に処理してから、４８時間及び７２時間培養し、ＭＴＴアッセイを遂行した結果を図３に示した。実施例１を処理した後、４８時間（３Ａ）及び７２時間（図３Ｂ）培養した実験結果全てで、比較例１に比べて乳癌細胞株であるＳＫ−ＢＲ−３細胞の増殖抑制率の高いことが確認された。また、実施例１と比較例１が４：１に混合された比較例２や、１：１に混合された比較例３に比べて、ＳＫ−ＢＲ−３細胞の増殖抑制率の高いことが確認された。 The results of treating Example 1 and Comparative Examples 1 to 3 with SK-BR-3 cells, which are human breast cancer cell lines, culturing for 48 hours and 72 hours, and performing the MTT assay are shown in FIG. In all the experimental results of culturing for 48 hours (3A) and 72 hours (FIG. 3B) after treating Example 1, the growth inhibition rate of SK-BR-3 cells, which is a breast cancer cell line, was higher than that of Comparative Example 1. It was confirmed that. In addition, the growth inhibition rate of SK-BR-3 cells is higher than that of Comparative Example 2 in which Example 1 and Comparative Example 1 are mixed 4: 1 and Comparative Example 3 in which Comparative Example 1 is mixed 1: 1. confirmed.
実験例２：ヒト乳癌（human breast cancer）細胞死滅誘導効果実験 Experimental example 2: Human breast cancer cell death-inducing effect experiment
（１）実験材料及び細胞培養 (1) Experimental materials and cell culture
牛胎兒血清（ＦＢＳ）と細胞培養培地を準備（Hyclone社）した。RT-PCR Kit及びTrizolはTakara Biotechnology CO., LTD.から、Annexin V-FITCはShanghai Biyuntian Biological Technology CO., LTD.,から入手した。プライマーはBeijing Aodingkangsheng Biological Technology CO., LTD.社に依頼してデザイン及び合成した。 Fetal bovine serum (FBS) and cell culture medium were prepared (Hyclone). The RT-PCR Kit and Trizol were obtained from Takara Biotechnology CO., LTD., And the Annexin V-FITC was obtained from Shanghai Biyuntian Biological Technology CO., LTD.,. Primers were designed and synthesized by commissioning Beijing Aodingkangsheng Biological Technology CO., LTD.
ヒトの癌細胞株であって、ヒト乳癌細胞株（human breast cancer cells）であるＭＣＦ−７細胞を中国科学アカデミーの上海細胞銀行から分譲を受けて、ＭＣＦ−７細胞は１０％ＦＢＳ、１００Ｕ／ｍＬペニシリン、及び１００μｇ／ｍＬストレプトマイシンが含まれたＭＥＭ（Minimum Essential Media）培地を用いて５％ＣＯ２及び９５％空気と湿気がある状態の培養器で細胞を培養した。培地は３日毎に交替した。 MCF-7 cells, which are human breast cancer cells, were sold from Shanghai Cell Bank of the Chinese Academy of Sciences, and MCF-7 cells are 10% FBS, 100U / Cells were cultured in a 5% CO 2 and 95% air and moisture incubator using MEM (Minimum Essential Media) medium containing mL penicillin and 100 μg / mL streptomycin. The medium was changed every 3 days.
（２）流細胞分析器（flow cytometry）利用 (2) Use of flow cytometry
実施例１の細胞死滅（apoptosis）誘導に対する効果を流細胞分析器を用いて評価した。６−ウェル培養ディッシュに１×１０５細胞／ウェル（cells／well）を分株し、２４時間の間培養した。２４時間後に、実施例１を０、１、３、６、９、１２、または１５μMになるように１０％ＦＢＳを含むＭＥＭ培地が入っている細胞に処理して２４時間の間培養した。２４時間後に細胞死滅を確認するためにAnnexin V-FITC kitを用いて細胞に処理し、自然的な細胞死との区別のためにＰＩ（propidium iodide）も共に処理した。この際、ＰＩとAnnexin V-FITC kitの利用方法に従って実験を進行した。Annexin V-FITC kitで処理した細胞をBD FACS calibur流細胞分析器を通じて細胞死滅程度を分析し、その結果を図４に示した。実施例１を処理した後、annexin VとＰＩとして標識された細胞を流細胞分析器で分析した結果（４Ａ）及びＰＩ対比annexin Vの量を分析して細胞死滅率（４Ｂ）を確認した結果、実施例１の処理濃度が増加することによって細胞死滅が増加することが確認された。 The effect of Example 1 on the induction of apoptosis was evaluated using a flow cell analyzer. 1 × 10 5 cells / well were separated into 6-well culture dishes and cultured for 24 hours. After 24 hours, Example 1 was treated into cells containing MEM medium containing 10% FBS to 0, 1, 3, 6, 9, 12, or 15 μM and cultured for 24 hours. After 24 hours, cells were treated with Annexin V-FITC kit to confirm cell death, and PI (propidium iodide) was also treated to distinguish it from natural cell death. At this time, the experiment proceeded according to the usage of PI and Annexin V-FITC kit. The cells treated with the Annexin V-FITC kit were analyzed for the degree of cell death through a BD FACS calibur flow cell analyzer, and the results are shown in FIG. After treating Example 1, the results of analyzing cells labeled as annexin V and PI with a flow cell analyzer (4A) and the results of analyzing the amount of annexin V compared to PI to confirm the cell mortality rate (4B). It was confirmed that the cell death increased as the treatment concentration of Example 1 increased.
（３）逆転写重合酵素連鎖反応（reverse transcription polymerase chain reaction、ＲＴ−ＰＣＲ）利用 (3) Use of reverse transcription polymerase chain reaction (RT-PCR)
実施例１の細胞死滅誘導に対する影響を確認するためにＲＴ−ＰＣＲを用いて細胞周期及び細胞死滅と関連した遺伝子であるcaspase-3、p21、cyclin E1、及びcyclin A2のｍＲＮＡ発現程度を確認した。６−ウェル培養ディッシュに１×１０５細胞／ウェル（cells／well）を分株し、２４時間の間培養した。２４時間後に、実施例１を０、１、３、６、９、１２、または１５μMになるように１０％ＦＢＳを含むＭＥＭ培地が入っている細胞に処理して２４時間の間培養した。２４時間後に細胞を収集した後、Trizol試薬を用いてＲＮＡを抽出した。抽出したＲＮＡを鋳型にし、以下の表３のプライマー及びRT-PCR kitを用いて遺伝子増幅を遂行し、アガロースゲルに電気泳動してcaspase 3、p21、cyclin E1、cyclin A2のｍＲＮＡ発現量の変化を確認し、その結果を図５に示した。この際、ローディング対照群にβ-actinの発現量も共に確認した。実施例１を処理した結果、細胞死滅と関連した細胞周期を調節する遺伝子であるp21とCyclin E1及び細胞死滅と関連したcaspase-3のｍＲＮＡ発現が実施例１の濃度増加によって増加する一方、細胞増殖に関連した細胞周期調節因子であるCyclin A2のｍＲＮＡ発現は減少することが確認された。
In order to confirm the effect of Example 1 on the induction of cell death, RT-PCR was used to confirm the cell cycle and the degree of mRNA expression of the genes associated with cell death, caspase-3, p21, cyclin E1 and cyclin A2. .. 1 × 10 5 cells / well were separated into 6-well culture dishes and cultured for 24 hours. After 24 hours, Example 1 was treated into cells containing MEM medium containing 10% FBS to 0, 1, 3, 6, 9, 12, or 15 μM and cultured for 24 hours. After collecting cells after 24 hours, RNA was extracted using Trizol reagent. Using the extracted RNA as a template, perform gene amplification using the primers in Table 3 below and the RT-PCR kit, and perform electrophoresis on an agarose gel to change the mRNA expression levels of
これを通じて、実施例１の六酸化四砒素が乳癌細胞の死滅を誘導することによって乳癌が治療できることが分かった。 Through this, it was found that breast cancer can be treated by inducing the death of breast cancer cells with tetraarsenic hexaoxide of Example 1.
実験例３：乳癌転移抑制効果確認試験 Experimental Example 3: Breast cancer metastasis suppression effect confirmation test
実験動物は特定病原菌及び呼吸器疾患から安全で、５週齢の体重が１８〜２０ｇ位であるbabl／c-nu雄ヌードマウス（nude mouse）を用いた。ヌードマウスは飲食と水を自由に摂取するようにし、１２時間の夜と１２時間の昼を周期にして７日間飼育した。 As the experimental animals, babl / c-nu male nude mice (nude mice), which are safe from specific pathogens and respiratory diseases and weigh about 18 to 20 g at 5 weeks of age, were used. Nude mice were allowed to eat, drink and drink freely, and were bred for 7 days with a cycle of 12 hours night and 12 hours day.
マウスにヒト乳癌細胞株であるＭＤＡ−ＭＢ−２３１細胞を皮下注射して移植し、７日間飼育した。７日後にマウスをランダムに分けた後、各々のマウスに実施例１及び比較例１の組成物を４．５ｍｇ／ｋｇになるように７日間経口投与した。この際、乳癌細胞移植後、なんにも処理しないマウスを対照群に用いた。組成物投与７日後にマウスから肺組織を取って肺に転移された癌細胞を数えて乳癌転移抑制程度を比較した。 MDA-MB-231 cells, which are human breast cancer cell lines, were subcutaneously injected into mice, transplanted, and bred for 7 days. After 7 days, the mice were randomly divided, and then the compositions of Example 1 and Comparative Example 1 were orally administered to each mouse at 4.5 mg / kg for 7 days. At this time, mice that were not treated after breast cancer cell transplantation were used as the control group. Seven days after administration of the composition, lung tissue was taken from mice, cancer cells metastasized to the lung were counted, and the degree of suppression of breast cancer metastasis was compared.
その結果、乳癌細胞を移植し、なんにも処理しない対照群の場合には移植された乳癌細胞が大部分肺に転移された一方、比較例１を処理した群と実施例１を処理した群の場合、肺への転移が抑制されたことを確認し、特に実施例１の場合、癌転移抑制率が９０％以上で、５０％癌転移抑制率を示す比較例１に比べて癌転移抑制効果が顕著に優れることを確認した。 As a result, in the case of the control group in which breast cancer cells were transplanted and nothing was treated, most of the transplanted breast cancer cells were metastasized to the lungs, while in the case of the group treated with Comparative Example 1 and the group treated with Example 1. It was confirmed that metastasis to the lung was suppressed, and in particular, in the case of Example 1, the cancer metastasis suppressing effect was 90% or more, and the cancer metastasis suppressing effect was higher than that of Comparative Example 1 showing a 50% cancer metastasis suppressing rate. It was confirmed that it was remarkably excellent.
実験例４：臨床試験 Experimental Example 4: Clinical trial
実施例１の組成物を用いて次のように臨床試験を施行した。 The clinical trial was carried out using the composition of Example 1 as follows.
２００６年に乳癌が発見されて病院治療と民間療法などを施行したが、肺、胸膜、骨、及び肝に転移されて、２０１４年５月に胸水と腹膜に腹水が溜まって数回に亘って胸水を抜いた。しかしながら、悪性胸水による深刻な呼吸困難により応急室及びホスピス病棟で酸素呼吸器を通じて呼吸したが、酸素不足によって蒼白症が表れ始めて、生存期間１週間位を残した状態で実施例１を毎日５ｍｇずつ３回（１５ｍｇ／日）経口服用した。 Breast cancer was discovered in 2006 and hospital treatment and folk remedies were performed, but it was metastasized to the lungs, pleura, bones, and liver, and ascites accumulated in the pleural effusion and peritoneum several times in May 2014. The pleural effusion was drained. However, due to severe dyspnea due to malignant pleural fluid, breathing was performed through an oxygen respiratory system in the emergency room and the hospice ward, but bleaching began to appear due to lack of oxygen, and Example 1 was administered at a rate of 5 mg daily with a survival period of about 1 week. It was taken orally 3 times (15 mg / day).
この患者の実施例１の投与前及び投与後８ケ月、１３ケ月、１７ケ月、２２ケ月のＣＴ写真は図６に示した。実施例１の投与前には右側肺と左側肺への転移によって気道が閉鎖されていたが、投与８ケ月、１３ケ月、１７ケ月、及び２２ケ月後には投与期間が増えることによって両側肺にいた癌のサイズが減ることを確認した。 CT photographs of this patient before and 8 months, 13 months, 17 months, and 22 months after administration of Example 1 are shown in FIG. Before the administration of Example 1, the airways were closed due to metastasis to the right and left lungs, but 8 months, 13 months, 17 months, and 22 months after the administration, the administration period was increased and the lungs were bilateral. It was confirmed that the size of the cancer was reduced.
臨床試験結果を通じて本発明の組成物は転移性乳癌の治療効果があると確認された。 Through the results of clinical trials, it was confirmed that the composition of the present invention has a therapeutic effect on metastatic breast cancer.
Claims (5)
前記六酸化四砒素は、以下の（i）乃至（iii）の特性
（i）格子定数：
ａ＝ｂ＝ｃ＝１１．０７３４Å
α＝β＝γ＝９０°
Ｖ＝１３５７．８２Å３
（ii）Ａｓ−Ｏ結合長さ：１．７８６Å
（iii）Ｏ−Ａｓ−Ｏ結合角：９８．３６゜
を有する六酸化四砒素の結晶多形ａが９９重量％以上である
ことを特徴とする乳癌予防または治療用薬学組成物。 A pharmaceutical composition for the prevention or treatment of breast cancer containing tetraarsenic hexaoxide (As 4 O 6 ) as an active ingredient.
The tetraarsenic hexaoxide has the following characteristics (i) to (iii) (i) Lattice constant :
a = b = c = 11.0734Å
α = β = γ = 90 °
V = 1357.82Å 3
(Ii) As—O bond length: 1.786 Å
(Iii) A pharmaceutical composition for preventing or treating breast cancer, wherein the polymorph a of tetraarsenic hexaoxide having an O—As—O bond angle: 98.36 ° is 99% by weight or more.
塩化ナトリウムを１００〜８００℃に加熱した後、冷却する第１工程；
塩化ナトリウムの上に三酸化二砒素（Ａｓ２Ｏ３）を上げた後、密閉状態で１００℃から１０００℃まで加熱した後、冷却する第２工程；
昇華された砒素を捕集する濾過紙で結晶化された結晶を分離する第３工程；及び
前記第３工程で得た結晶を第２工程の三酸化二砒素の代わりに使用して第２工程及び第３工程を４〜１０回繰り返して六酸化四砒素結晶を得る第４工程；
を通じて製造され、
前記第４工程で得られる六酸化四砒素は、前記結晶多形ａが９９重量％以上である
ことを特徴とする乳癌予防または治療用薬学組成物の製造方法。 The method for producing a pharmaceutical composition for preventing or treating breast cancer according to claim 1.
First step of heating sodium chloride to 100-800 ° C. and then cooling;
The second step of raising arsenic trioxide (As 2 O 3 ) on sodium chloride, heating it from 100 ° C to 1000 ° C in a sealed state, and then cooling it;
The third step of separating the crystals crystallized with a filter paper that collects the sublimated arsenic; and the second step of using the crystals obtained in the third step instead of the diarsenic trioxide in the second step. And the third step is repeated 4 to 10 times to obtain a tetraarsenic hexaoxide crystal;
Is produced through,
The fourth arsenic hexoxide obtained in step, the manufacturing method of the crystalline polymorph a is breast cancer prevention or therapeutic pharmaceutical composition you characterized in that 99 wt% or more.
請求項１に記載の乳癌予防または治療用薬学組成物。 The pharmaceutical composition for preventing or treating breast cancer according to claim 1, wherein the tetraarsenic hexaoxide has a purity of 99.9% or more.
請求項１に記載の乳癌予防または治療用薬学組成物。 The crystal polymorph a is an X-ray powder diffraction spectrometer, and is displayed at a speed of 1 ° / min (scan step 0.02 °) at a diffraction angle of 2θ = 10 to 50 ° when the light source wavelength is 1.5406 Å. The breast cancer prevention according to claim 1, wherein the peaks are 13.84, 27.88, 32.32, 35.3, 39.84, 42.38, 46.34, 48.6, and 49.34. Or a therapeutic pharmaceutical composition.
前記六酸化四砒素は、以下の（i）乃至（iii）の特性
（i）格子定数：
ａ＝ｂ＝ｃ＝１１．０７３４Å
α＝β＝γ＝９０°
Ｖ＝１３５７．８２Å３
（ii）Ａｓ−Ｏ結合長さ：１．７８６Å
（iii）Ｏ−Ａｓ−Ｏ結合角：９８．３６゜
を有する六酸化四砒素の結晶多形ａが９９重量％以上である
ことを特徴とする乳癌転移抑制用薬学組成物。 A pharmaceutical composition for suppressing breast cancer metastasis containing tetraarsenic hexaoxide (As 4 O 6 ) as an active ingredient.
The tetraarsenic hexaoxide has the following characteristics (i) to (iii) (i) Lattice constant :
a = b = c = 11.0734Å
α = β = γ = 90 °
V = 1357.82Å 3
(Ii) As—O bond length: 1.786 Å
(Iii) A pharmaceutical composition for suppressing breast cancer metastasis, wherein the polymorph a of tetraarsenic hexaoxide having an O—As—O bond angle: 98.36 ° is 99% by weight or more.
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| KR1020160155228A KR101834366B1 (en) | 2016-11-21 | 2016-11-21 | Pharmaceutical composition for prevention or treatment of breast cancer comprising polymorphic form of tetraarsenic oxide and preparation method thereof |
| PCT/KR2017/013148 WO2018093215A1 (en) | 2016-11-21 | 2017-11-17 | Pharmaceutical composition for preventing or treating breast cancer including crystalline polymorph of tetraarsenic hexoxide, and method for producing same |
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| KR101844049B1 (en) * | 2016-12-05 | 2018-03-30 | 주식회사 케마스 | Pharmaceutical composition for prevention or treatment of liver cancer comprising polymorphic form of tetraarsenic oxide |
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